Sedation and analgesia final 31July2010

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AN ESICM MULTIDISCIPLINARY DISTANCE LEARNING PROGRAMME 
FOR INTENSIVE CARE TRAINING 
 
 
 
 
 
Sedation and analgesia 
 
Skills and techniques 
 
 
Update July 2010 
 
 
 
 
Module Author (Update 2010) 
 
Mauro ODDO MD, Staff Physician, Department of Intensive Care 
Medicine, Centre Hospitalier Universitaire Vaudois 
(CHUV), University Hospital and Faculty of Biology 
and Medicine, Lausanne, Switzerland 
 
 
 
Module Authors (Update 2005) 
 
Gilbert R Park Director, The John Farman Intensive Care Unit, 
Addenbrooke's NHS Trust Hospital, Cambridge, 
UK 
 
Michael Lane Research Nurse, The John Farman Intensive 
Care Unit, Addenbrooke's NHS Trust Hospital, 
Cambridge, UK 
 
 
 
Module Reviewers Arturo Chieregato, Lia Fluit, 
Marek Mirski, Janice Zimmerman 
 
Section Editor Giuseppe Citerio 
 
 
 
 
Sedation and analgesia 
Update July 2010 
 
Editor-in-Chief Dermot Phelan, Intensive Care Dept, 
Mater Hospital/University College Dublin, Ireland 
Deputy Editor-in-Chief Francesca Rubulotta, Imperial College, Charing 
Cross Hospital, London, UK 
Medical Copy-editor Charles Hinds, Barts and The London School of 
Medicine and Dentistry 
Editorial Manager Kathleen Brown, Triwords Limited, Tayport, UK 
Business Manager Estelle Flament, ESICM, Brussels, Belgium 
Chair of Education and Training 
Committee 
Hans Flaatten, Bergen, Norway 
 
 
PACT Editorial Board 
 
Editor-in-Chief Dermot Phelan 
Deputy Editor-in-Chief Francesca Rubulotta 
Acute respiratory failure Anders Larsson 
Cardiovascular dynamics Jan Poelaert/Marco Maggiorini 
Neuro-intensive care and Emergency 
medicine 
Giuseppe Citerio 
HSRO/TAHI Carl Waldmann 
Environmental hazards Janice Zimmerman 
Systemic inflammation and 
Sepsis/Infection 
Johan Groeneveld 
Metabolism, endocrinology, 
nephrology, nutrition 
Charles Hinds 
Perioperative ICM and surgery Position Vacant 
ETC/Ethics Gavin Lavery 
Education and assessment Lia Fluit 
Consultant to the PACT Board Graham Ramsay 
 
 
Copyright© 2010. European Society of Intensive Care Medicine. All rights reserved. 
 
 
 
Contents 
Introduction ..................................................................................................................................................... 0 
What is sedation?......................................................................................................................................... 0 
1. Identifying patients’ needs; approach to sedation and pain relief ............................................................... 1 
Relief of pain ................................................................................................................................................. 1 
Mechanical ventilation .................................................................................................................................2 
Fear and anxiety............................................................................................................................................2 
A good night’s sleep ......................................................................................................................................3 
Amnesia.........................................................................................................................................................4 
Humanitarian concerns................................................................................................................................5 
Target-based sedation and analgesia ...........................................................................................................7 
Implementation of protocols for targeted sedation.................................................................................7 
Drugs.............................................................................................................................................................8 
Hypnotic drugs .............................................................................................................................................9 
Benzodiazepines .....................................................................................................................................10 
Benzodiazepine antagonists................................................................................................................... 12 
Propofol .................................................................................................................................................. 13 
Ketamine................................................................................................................................................. 14 
Thiopental (Thiopentone) ...................................................................................................................... 14 
Alpha-2 agonists..................................................................................................................................... 15 
Neuroleptics ........................................................................................................................................... 16 
Analgesics.................................................................................................................................................... 18 
Opioids.................................................................................................................................................... 18 
Non-steroidal anti-inflammatory drugs ................................................................................................23 
2. Techniques and routes of administration...................................................................................................24 
Other routes of administration...................................................................................................................27 
Epidural infusion....................................................................................................................................27 
Combination of drugs .................................................................................................................................27 
3. Neuromuscular blockade ............................................................................................................................29 
Specific agents............................................................................................................................................ 30 
Atracurium ............................................................................................................................................ 30 
Cisatracurium........................................................................................................................................ 30 
Pancuronium ......................................................................................................................................... 30 
Vecuronium ............................................................................................................................................ 31 
Rocuronium............................................................................................................................................ 31 
Suxamethonium (Succinylcholine)........................................................................................................32 
Hazards of using neuromuscular blockers ............................................................................................32 
4. Measuring and monitoring the effects of sedatives, analgesics and neuromuscular blockers..................34 
Level of analgesia........................................................................................................................................34 
Pain assessment: communicative patients ............................................................................................34Pain assessment: non-communicative patients ....................................................................................34 
Level of sedation .........................................................................................................................................35 
Haemodynamics.....................................................................................................................................36 
Neuromonitoring, including electroencephalograph ............................................................................37 
Lower oesophageal tone........................................................................................................................ 38 
Effect of neuromuscular blockers.............................................................................................................. 38 
5. Managing adverse effects and cost/benefit issues of sedative drugs ........................................................ 40 
Metabolites ............................................................................................................................................ 40 
Solvents................................................................................................................................................... 41 
Drug interactions....................................................................................................................................43 
Unexpected effects .................................................................................................................................43 
Anti-depressants ....................................................................................................................................44 
Neuromuscular blockers.............................................................................................................................44 
Effects of age and disease.......................................................................................................................45 
Modifying approach in response to cost/benefit issues.............................................................................45 
Conclusion.......................................................................................................................................................47 
Self-assessment Questions............................................................................................................................. 48 
Patient challenges............................................................................................................................................52 
 
 
Contents 
LEARNING OBJECTIVES 
After studying this module on Sedation, you should be able to: 
1. Outline an approach to sedation and relief of pain based on the patient's needs 
2. Identify different techniques and routes of drug administration 
3. Use appropriate monitoring tools and manage adverse drug effects 
4. Modify interventions based on cost/benefit analyses 
FACULTY DISCLOSURES The author of this module has not reported any disclosures. 
 
DURATION 5 hours 
 
 
 
 
 
 
Introduction 
INTRODUCTION 
 
What is sedation? 
 
The need for sedation is multifactorial. Appropriate analgesia is frequently the key 
requirement. 
 
Sedation comes from the Latin sedare – to soothe. Nearly all critically ill patients 
will need some kind of 'soothing'. Consideration of the complexity of the Critical 
Care scenario allows appreciation of the diverse nature of a patient’s need for 
sedation. 
 
Sedation is a broad term. It is often assumed to mean just hypnosis, but it is much 
more than this and may include: 
 
• Pain relief and reduction of discomfort caused by intensive care 
technology, e.g. tubes and ventilators and the obligate posture of 
critically ill patients 
• Relief from fear and anxiety 
• The desire for a good night's sleep 
• Reduction of awareness (hypnosis) 
• Reduction of stimulation and the consequent changes in arterial 
pressure, ventilation/PaCO2, shivering, cough, posturing – all of which 
are potentially associated with increases in cerebral metabolic 
consumption and intracranial pressure, particularly in the neurological 
intensive care patient 
• Control of delusional agitation/delirium. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.1 
 
1. IDENTIFYING PATIENTS’ NEEDS; APPROACH TO 
SEDATION AND PAIN RELIEF 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.310–311. 
 
Prior to making specific decisions regarding an individual patient's sedation 
requirements, consider the following: 
 
• Clearly define the individual patient's problem – need for analgesia, 
anxiolysis, antipsychosis, or any combination of these 
• Determine if sedation is the primary requirement 
• Estimate the period of time for which sedation will be required 
• Administer the drug that has the best pharmacokinetic profile. This 
profile should be individualised in accordance with patient co-
morbidities and primary disease (neurological, septic, cardiac), as well 
as medical vs postoperative, surgical ICU admission. Further details of 
these universally applicable recommendations are contained in the 
following references. See the guidelines on the SCCM website, 
http://www.sccm.org [LearnICU/Administration/Administrative 
Guidelines]. 
 
Pandharipande P, Ely EW, editors. Sedation and analgesia in the ICU – 
pharmacology, protocolization, and clinical consequences. Crit Care Clin 
2009; 25(3): 431–636. 
(http://www.sciencedirect.com/science/article/B7RMB-4WN9T8P-
1/2/bfaba97aca1650cdb7918976ab875537) 
Nasraway SA, Jacobi J, Murray MJ, Lumb PD. Sedation, analgesia, and 
neuromuscular blockade of the critically ill adult: Revised clinical practice 
guidelines for 2002. Crit Care Med 2002; 30: 117-118. No abstract available. 
PMID 11902252 
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET et al. Clinical 
practice guidelines for the sustained use of sedatives and analgesics in the 
critically ill adult. Crit Care Med 2002; 30: 119-141. PMID 11902253 
 
Amongst the various factors leading to the need for sedation/analgesia in 
individual patients, the following are the most common: 
 
Relief of pain 
 
This is one of the commonest causes of patient distress. Pain may be suffered as a 
consequence of surgery, trauma or inflammation, such as pleurisy, peritonitis or 
pericarditis. Pain can be relieved by administering analgesics. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.2 
 
 
Other causes of discomfort include the presence of a tracheal tube, full bladder or 
bowel, chest tubes and immobility. Hypnotic drugs must not be used in an attempt 
to reduce pain because any periods of consciousness the patient has are then filled 
with pain. Recent data suggest that ICU patients often suffer from inadequate 
analgesia. Daily pain assessment and optimisation of analgesia may reduce the 
duration of ventilation and ICU length of stay. 
 
Payen JF, Chanques G, Mantz J, Hercule C, Auriant I, Leguillou JL, et al. Current 
practices in sedation and analgesia for mechanically ventilated critically ill 
patients: a prospective multicenter patient-based study Anesthesiology 2007; 
106(4): 687–695. PMID 17413906 
Payen JF, Bosson JL, Chanques G, Mantz J, Labarere J; DOLOREA Investigators. 
Pain assessment is associated with decreased duration of mechanical 
ventilation in the intensive care unit: a post Hoc analysis of the DOLOREA 
study Anesthesiology 2009; 111(6): 1308–1316. PMID 19934877 
 
Mechanical ventilation 
 
 
Mechanically ventilated patients may have additional needs, e.g. 
 
 
• An antitussive effect to help the patient to tolerate the presence of a 
tracheal tube and tracheal suction without prolonged periods of 
coughing. 
• Tolerance of mechanical ventilation. Althoughmodern ventilators that 
allow synchronised spontaneous breathing have reduced the need for 
sedation, some is usually needed, particularly following initiation of 
assisted ventilation. 
 
 Keep these factors in mind as you consider the sedation requirements of an 
individual patient. Remember that these requirements, perhaps more than any 
other facet of critical care, are subject to wide individual variation. 
 
Fear and anxiety 
 
The relief of fear and anxiety at an early stage is a key therapeutic objective. 
 
• Many critically ill patients are convinced they are going to die. 
Reassurance from the patient's caregiver may help to overcome this fear. 
Discussions at the patient's bedside should avoid issues such as 
withdrawal of futile, invasive treatment, outcomes and possible 
diagnosis of cancer to prevent unnecessary distress. 
No patient should be 
allowed to 'fight the 
ventilator' 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.3 
 
• Some critically ill patients will be sufficiently alert to be worried about 
the impact of their illness on their family and other loved ones. 
Involvement of social services may be helpful in this respect. 
• If the patient has come into an ICU following an accident, other 
members of the family may have been injured or even killed. Some 
patients will therefore be bereaved and may benefit from professional 
counselling. 
• Many patients cannot talk and are unable to write legibly. The inability 
to communicate increases frustration and may add to the patient’s fear 
and anxiety. 
• The unfamiliar environment of the ICU combined with the presence of 
numerous strangers is a further source of stress. 
 
It is important to remember that a sympathetic and thorough explanation, perhaps 
combined with a visit from a family member, may be all that is required. 
See the following references for further information. 
 
Pandharipande P, Ely EW, editors. Sedation and analgesia in the ICU – 
pharmacology, protocolization, and clinical consequences. Crit Care Clin 
2009; 25(3): 431–636. 
(http://www.sciencedirect.com/science/article/B7RMB-4WN9T8P-
1/2/bfaba97aca1650cdb7918976ab875537) 
PACT module on Communication skills 
 
A good night’s sleep 
 
Patients treated in ICUs are constantly being disturbed. Not only are many 
mechanically ventilated but, there is also the need to attend to bodily functions 
such as eye, mouth and skin care. In addition, alarms are disruptive and can 
provoke considerable anxiety. As a consequence sleep deprivation is common and 
the normal day/night sleep cycle is almost universally disturbed. This disruption 
can be reduced by darkening the room at night, maximising quiet periods and 
minimising direct patient disturbance at night. Although the ICU environment 
itself contributes greatly towards sleep disruption, other factors including drugs 
e.g. sedatives, analgesics, corticosteroids, phenytoin, clonidine, beta-blockers also 
interfere with normal sleep patterns. Efforts aimed at maintaining adequate sleep 
are essential since sleep deprivation predisposes to delirium, which in turn, may 
independently increase morbidity and mortality. 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.322–323. Prevention. 
Weinhouse GL, Schwab RJ, Watson PL, Patil N, Vaccaro B, Pandharipande P, at al. 
Bench-to-bedside review: delirium in ICU patients - importance of sleep 
deprivation Crit Care 2009; 13(6): 234. PMID 20053301 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.4 
 
Freedman NS, Gazendam J, Levan L, Pack AI, Schwab RJ. Abnormal sleep/wake 
cycles and the effect of environmental noise on sleep disruption in the 
intensive care unit Am J Respir Crit Care Med 2001; 163(2): 451–457 PMID 
11179121 
 
 We all need a good night's sleep. Think about how you feel after a busy night 
on call; imagine what it must be like to be awake night after night. Before starting night 
sedation, however, it is important to ask the patient whether they feel tired. It is a 
common belief that everyone needs eight hours sleep every night. For some four hours 
may be sufficient, even when they are ill. 
 
Amnesia 
 
Amnesia is often an unintended consequence of administering hypnotic drugs. 
Previously, amnesia was thought to be harmless, but it is now recognised as being 
potentially harmful to the long-term psychological well-being of the patient. 
Amnesia is rarely desirable, indeed some patients may find being able to remember 
their time in intensive care helpful. 
 
 The occurrence of neuro-cognitive disorders/post-traumatic stress 
disorders after ICU has been linked to (deep) incl. lorazepam/midazolam sedation 
and to diminished memory of ICU, particularly if memory is absent or delusional in 
character. See link to ESICM Flash Conference: E Azoulay ‘Post-ICU cognitive 
dysfunction’ ESICM congress, Vienna 2009. 
 
 
In the following references you will find further information about the relationship 
between memories of intensive care and the level of anxiety and incidence of post-
traumatic stress disorder-related symptoms after discharge. 
 
Jones C, Griffiths RD, Humphris G. Skirrow PM. Memory, delusions and the 
development of acute posttraumatic stress disorder-related symptoms after 
intensive care. Crit Care Med 2001; 29(3): 573–580. PMID 11373423 
Granja C, Gomes E, Amaro A, Ribeiro O, Jones C, Carneiro A, et al; JMIP Study 
Group. Understanding posttraumatic stress disorder-related symptoms after 
critical care: the early illness amnesia hypothesis. Crit Care Med 2008; 
36(10): 2801-2809. PMID 18766108 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.5 
 
Humanitarian concerns 
 
 
 
It is an easy option to sedate patients pharmacologically. Attending 
to your patient's humanitarian needs, however, is of paramount 
importance. Drugs should be seen as complementing not 
substituting for this aspect of patient care. 
 
The following points should be borne in mind: 
 
• Environment – day and night pattern of activities in cheerful, pleasant 
and welcoming surroundings – attempting as far as possible to promote 
a near-normal atmosphere and minimise the hospital/institutional 
ambience. 
 
• Reassurance – kind words may relieve anxiety. 
 
• Explanation – communication should be both informative and 
enlightening. 
 
• Careless discussion in front of an awake patient can cause anxiety. 
 
• Full bladder, distended bowels, and other irritants such as an itch from a 
plaster cast are all potent causes of discomfort in the critically ill patient 
that are best relieved by dealing with the cause, rather than giving 
sedative drugs. 
 
Drugs may not be the best 
approach to relieving 
anxiety 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.6 
 
• In comatose patients – flexed elbows and scheduled passive 
mobilisation with change of position is important. 
 
• A quiet darkened room with the television or music system turned off, if 
necessary combined with ear-plugs and an eye-shade, will sometimes 
provide the patient with a better night's sleep than a hypnotic. 
 
• A daily plan for the patient a day in advance, even if this only includes 
simple activities such as washing, watching television and a visit from 
relatives. Nothing is more demoralising than waking up to a day of 
interminable emptiness and uncertainty. 
 
• During recovery from prolonged critical illness, attempts should be 
made to restore to the patient some degree of self-control over his or her 
immediate environment. This should include psychosocial aspects e.g. in 
some countries this might include alcoholic drinks as appetite 
stimulants. 
 
• Efforts to maintain physiological circadian rhythm (room with a 
window, normal environmental light) may improve quality of sleep 
thereby reducing sleep deprivation and the risk of delirium.You will wish to carefully consider all these points and their possible importance in 
individual patient care before rushing to the drug cupboard. 
 
 Sedative practice in the ICU is constantly evolving. Clarification of the 
needs of individual patients and increased awareness of the adverse effects of 
sedative drugs are increasingly appreciated as being relevant. 
 
Q. Why is it important for an ICU to have an agreed 'sedation policy'? 
 
A. Sedation policies help to ensure that the correct drug is given to the right patient, at the 
right time and in the right dose. In addition, they promote the efficient utilisation of 
resources. As with all 'policies' for managing the critically ill, they need to be applied 
intelligently. 
 
Q. Why is it important to determine and respond to individual patients' 
views on their needs for sedation/analgesia? How would you ensure 
this happens? 
 
A. Sedation and analgesia are given primarily to maintain patient comfort. During 
conscious sedation, titration of medication can be managed via direct patient feedback. 
Deeper levels of sedation are sometimes required to optimise patient management; specific 
sedation scales are typically used to titrate sedative dose. Patient surveys following transfer 
from the ICU can be used to evaluate the success of ICU pain management and anxiolysis 
protocols. 
 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.7 
 
Q. A patient's needs for sedation will vary from time to time. Consider 
six possible factors that might account for such variation. 
 
A. 
• Changes in the patient's illness severity 
• Need for further surgery 
• Changes in the mode of ventilatory support 
• Tolerance to drugs 
• Changes in renal and liver function resulting in altered drug elimination 
• Toxicity of the sedative agent, or its solvent 
• Need for patient transfer (e.g. CT scan). 
 
 In the next ten patients under your care in the ICU, determine what changes in the 
sedative regime are required to accommodate the factors mentioned above. 
 
Target-based sedation and analgesia 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.311–312. Assessing the level of 
sedation. 
Sedation management in ICU. In: Waldmann C, Soni N, Rhodes A, editors. Oxford 
Desk Reference: Critical Care. Oxford: Oxford University Press; 2008. p. 208. 
ISBN 13: 9780199229581 
 
The use of a structured approach to sedation management, including guidelines, 
protocols, and algorithms can promote evidence-based care, reduce variation in 
clinical practice, and systematically reduce the likelihood of excessive and/or 
prolonged sedation. Many published sedation protocols have been tested in 
controlled clinical trials, often demonstrating benefits such as shorter duration of 
mechanical ventilation, reduced ICU length of stay, and/or superior sedation 
management compared to non-protocol based care. Implementation of sedation 
algorithms in ICUs is a challenging process for which sufficient resources must be 
allocated. 
 
Implementation of protocols for targeted sedation 
 
Continuous infusion sedation (CIS) is an independent risk factor for longer 
duration of mechanical ventilation and longer ICU length of stay. Daily 
interruption of sedation (DIS) with re-titration to minimise prolonged sedative 
effects is therefore recommended. DIS can be coupled with a daily spontaneous 
breathing trial. Use of sedation algorithm or protocol is essential. Important 
components include choice of sedatives and analgesics, tools to measure pain, 
agitation, sedation and patient–ventilator synchrony, and protocol design. 
Principles for developing and implementing protocolised sedation management 
can be summarised as follows: 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.8 
 
 
• Perform multidisciplinary development and implementation 
• Establish treatment goals and specific targets that are frequently re-
evaluated 
• Measure key components (pain, agitation, sedation) using validated 
scales 
• Select medications based on key characteristics and evidence 
• Incorporate important patient considerations in selection of medication 
and management, including safety screening for at-risk populations 
• Design the protocol to prevent over-sedation yet control pain and 
agitation 
• Promote multidisciplinary acceptance and integration into routine care 
• Institute daily interruption of sedation and analgesia, and emphasise the 
importance of intermittent use of sedatives and analgesics. 
 
 Although daily interruption of sedation has been demonstrated to be of 
benefit in certain ICU situations, it is not necessarily applicable for universal use 
e.g. in patients with intracranial hypertension. See Task 2 on daily interruption of 
sedation (DIS). 
 
Use of a sedation algorithm is associated with shorter duration of mechanical 
ventilation, and/or shorter ICU length of stay. Other benefits include more ‘on-
target’ sedation, less pain, reduced direct costs or medication use, less patient–
ventilator asynchrony, and decreased incidence of ventilator-associated 
pneumonia. 
 
Sessler CN, Pedram S. Protocolized and target-based sedation and analgesia in the 
ICU. Crit Care Clin. 2009 Jul;25(3):489-513, viii. PMID 19576526 
(http://www.sciencedirect.com/science/article/B7RMB-4WN9T8P-
8/2/10e4453105326c45b0af595acf1f05d3) 
 
Drugs 
 
Drugs, carefully considered and regularly reviewed, play a vital role. In most 
instances and particularly on admission to ICU, patients will require some form of 
pharmacological intervention to help them cope with pain, anxiety or sleeplessness. 
 
You may find the following texts of particular value in this connection: 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.9 
 
 
Pharmacology and toxicology; Sedatives and hypnotics. In: Fink M, Abraham E, 
Kochanek P, Vincent JL, editors. Textbook of critical care. 5th ed. 
Philadelphia: WB Saunders. ISBN 0721603351 
 
Although there are two broad categories of drugs: sedatives and analgesics, it is 
clear that there is considerable overlap between the two. The analgesic, morphine, 
for example, causes sedation while the relief of agitation with a drug such as 
clonidine may reduce pain. Some of the overlapping effects of drugs are illustrated 
below. 
 
Note: in figure below, new short-acting alpha-2 agonists (i.e. dexmedetomidine) 
are already available in the US and should soon become available in many 
European countries. 
 
 
 
Hypnotic drugs 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.315–317. Sedatives. 
 
 
Many of the sedative or hypnotic agents used in intensive care are 
also used in anaesthetic practice. Although valuable insight into 
their actions can be obtained in the operating room, they may 
behave differently when used in the critically ill. 
 
 
 
 A dose that is suitable for use in a fit and healthy patient needing anaesthesia 
may be dangerous in a critically ill patient of similar age, height and weight. 
 
Operating room 
experience with 
hypnotics may 
not be 
transferable to 
the ICU 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.10 
 
Some of the hypnotic agents currently available are listed below, together with 
selected properties and metabolic actions. 
 
 
 
Benzodiazepines 
 
Benzodiazepines are particularly effective for relieving anxiety and producing 
amnesia and hypnosis. Their effects are mediated by depressing the excitability of 
the limbic system through reversible binding at the gamma aminobutyric acid 
(GABA)-benzodiazepine receptor complex. They have minor muscle relaxant 
properties that are mediated by the glycine receptors in spinal and supraspinal 
regions. All produce some degree of cardiovascular and respiratory depression. 
 
The range of availablebenzodiazepines includes the relatively old drug, diazepam, 
and the much more commonly used midazolam. 
 
Midazolam 
 
Midazolam is water soluble at pH 4 and fat soluble at pH 7. It has three principal 
metabolites, 1-hydroxymidazolam (having one-fortieth of the activity of the parent 
drug), 4-hydroxymidazolam, and 1,4-hydroxymidazolam. In the critically ill patient 
the 1-hydroxy metabolite may accumulate. The normal elimination half-life is two 
hours but may increase to 24 hours in the critically ill. A special caution should be 
applied in the use of midazolam due to its propensity to induce tachyphylaxis and 
withdrawal syndrome. This is particularly true in children. The risk for 
accumulation and prolonged sedation is higher in patients with kidney or liver 
failure. 
 
Q. Do special solvents present difficulties? Explain you answer. 
 
A. Many drugs have to be dissolved in solvents other than water. When large amounts are 
given to patients, especially those with liver or renal failure, these solvents can accumulate 
and cause toxicity. For further information read Task 5. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.11 
 
Lorazepam 
 
This drug has a half-life of approximately 14 hours. Because lorazepam metabolites 
are glucuronides they are considered to be inactive. Glucuronidation pathways are 
spared in liver disease and lorazepam may therefore be useful in such conditions. 
However, it is solubilised in propylene glycol and toxicity may arise if the infusion 
is prolonged or delivered at high doses. Thus repeated intravenous boluses are 
preferred to continuous infusion when possible. Lorazepam has found favour as an 
alternative to midazolam, particularly in North America. However, recent studies 
suggest that lorazepam (and therefore probably other benzodiazepines) is an 
independent risk factor for delirium in mechanically ventilated patients. 
 
Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, et al. 
Lorazepam is an independent risk factor for transitioning to delirium in 
intensive care unit patients Anesthesiology 2006; 104(1): 21–26. PMID 
16394685 
 
Diazepam 
 
This drug has fallen into disuse because of concern about its long-acting 
metabolites. One in particular (nor desmethyl diazepam) has a longer elimination 
half-life than the parent drug. Being lipid soluble, diazepam has to be administered 
in a special solvent e.g. propylene glycol (which is an irritant) or soya bean extract. 
This agent is no longer recommended in general critical care practice but may have 
a role in neuro-critical care where its pharmacokinetic properties may not, in some 
patients, be considered to add to the weaning time and may attenuate withdrawal 
symptoms. Daily interruption of sedation (DIS – see Task 2) protocols may be 
utilised to limit oversedation. 
 
Q. Why does prolonged sedation matter? 
 
A. Unexpected and prolonged sedation is potentially dangerous. The duration of 
mechanical ventilation, the risk of organ failure and the incidence of tracheostomy are all 
increased. Unnecessary investigations, such as a head CT may be performed. ICU stay is 
prolonged and costs are increased. For further information read Task 5. 
 
Q. What is the relationship between the half-life of a sedative agent and 
duration of effect? 
 
A. Half-life is a pharmacokinetic term, while duration of action refers to the 
pharmacodynamics of a drug effect. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.12 
 
 
Park GR. Molecular mechanisms of drug metabolism in the critically ill Br J Anaesth 
1996; 77(1): 32–49 Review. PMID 8703629 
 
The American College of Critical Care Medicine (ACCM) and the Society of Critical 
Care Medicine (SCCM) recommend propofol or midazolam for short-term sedation 
use. For further details read: 
 
 
Nasraway SA Jr, Jacobi J, Murray MJ, Lumb PD; Task Force of the American College 
of Critical Care Medicine of the Society of Critical Care Medicine and the 
American Society of Health-System Pharmacists, American College of Chest 
Physicians. Sedation, analgesia, and neuromuscular blockade of the critically 
ill adult: revised clinical practice guidelines for 2002 Crit Care Med 2002; 
30(1): 117–118. PMID 11902252 
 
The following table is a guide to dosage of these three agents for longer term 
sedation in critically ill adults. 
 
Benzodiazepine antagonists 
 
Flumazenil 
 
Flumazenil is a benzodiazepine antagonist with high affinity for, but no activity at 
the benzodiazepine receptor. Its half-life (approximately 60 minutes) is shorter 
than that of midazolam and lorazepam, and reversal of sedation (which can be 
abrupt) will be followed by resedation unless further doses are administered or 
flumazenil is given by infusion. 
 
The IV dose starts at 0.2–1 mg, which is titrated to patient response. Flumazenil 
can cause benzodiazepine withdrawal and may induce seizures so it should be used 
with caution and is contraindicated in neurological intensive care patients 
especially in those at risk of seizure and with measured or suspected intracranial 
hypertension. Any neurological examination in patients receiving benzodiazepines 
should await drug washout as a clinical exam undertaken while the patient is under 
the influence of flumazenil may be distorted and hazardous. For further reading on 
this subject see: 
 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.13 
 
 
Nasraway SA Jr, Jacobi J, Murray MJ, Lumb PD; Task Force of the American College 
of Critical Care Medicine of the Society of Critical Care Medicine and the 
American Society of Health-System Pharmacists, American College of Chest 
Physicians. Sedation, analgesia, and neuromuscular blockade of the critically 
ill adult: revised clinical practice guidelines for 2002 Crit Care Med 2002; 
30(1): 117–118. PMID 11902252 
 
Propofol 
 
This intravenous anaesthetic agent also acts on the gamma aminobutyric acid 
(GABA) receptor. Propofol has cardiorespiratory depressant effects and may 
produce significant hypotension in hypovolaemic or septic patients. It is made 
soluble in soya bean extract. The potential for this solubilising agent to cause harm 
is described under solvents in Task 5. 
 
The effects of propofol start and end quickly. Metabolised mostly by the liver, 
propofol metabolites are inactive. Special caution is warranted during hypothermia 
and in any condition of splanchnic hypoperfusion. In such conditions the rate of 
hepatic metabolism declines with the resultant risk of increased serum 
concentrations. 
 
There are probably also significant extra hepatic sites of metabolism. The drug is 
usually given by infusion (maximum rate 4 mg/kg/h) but its use for long-term 
sedation (over 48hrs) is generally not recommended. 
 
Propofol is particularly suitable for neurological intensive care patients. It is 
recommended as a first-line sedative after neurotrauma within the Brain Trauma 
Foundation guidelines. 
 
 
 
 
 
 
Brain Trauma Foundation; American Association of Neurological Surgeons; 
Congress of Neurological Surgeons; Joint Section on Neurotrauma and 
Critical Care, AANS/CNS, Bratton SL, Chestnut RM, Ghajar J, McConnell 
Hammond FF, Harris OA, et al. Guidelines for the management of severe 
traumatic brain injury. XI. Anesthetics, analgesics, and sedatives. J 
Neurotrauma 2007; 24 Suppl 1:S71-76. No abstract available. PMID: 
17511550 
Check your national regulatory authority or the European Medicines 
Agency (www.ema.europa.eu) for specific advice on the regulatory limit 
to infusion therapy in your jurisdiction 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.14 
 
Ketamine 
 
Ketamine is an anaesthetic agent similar in structure to phencyclidine. Its effects 
are mediated by N-methyl-D-aspartate (NMDA) receptor stimulation. Because it 
releases catecholamines, ketamine causes an increase in heart rate andarterial 
blood pressure in normal patients. This may not occur in the critically ill. Ketamine 
increases cerebral blood flow and metabolism and may thus raise intracranial 
pressure. Ketamine is also a bronchodilator and has been used in the treatment of 
severe acute asthma. Because one of its major adverse effects is nightmares, 
ketamine should always be combined with a benzodiazepine. 
 
The dose is 25–50 mg as an intravenous bolus with an infusion rate of 10–30 
mg/h. When given as an infusion it may be combined with midazolam in a 10:1 
mixture (ketamine:midazolam). 
 
Aroni F, Iacovidou N, Dontas I, Pourzitaki C, Xanthos T. Pharmacological aspects 
and potential new clinical applications of ketamine: reevaluation of an old 
drug. J Clin Pharmacol 2009; 49(8): 957–964. PMID 19546251 
 
 
A 65-year-old lady fell asleep in front of the fire. She sustained burns to her legs 
and suffered smoke inhalation injury. Skin grafting and mechanical ventilation 
were required. After two weeks she was weaned from the ventilator, but still needed 
to return to the operating theatre for wound dressings. On each occasion she was 
given a general anaesthetic and required mechanical ventilation afterwards for 
several hours. Subsequently the dressings were changed in the ICU using a mixture 
of ketamine and midazolam. For pain relief a 10:1 mixture (ketamine:midazolam) 
was delivered using a patient-controlled analgesia system (PCAS). This gave good 
analgesia without respiratory depression and avoided unnecessary, repeated 
general anaesthetics. 
 
Thiopental (Thiopentone) 
 
Thiopental is a barbiturate developed as an anaesthetic induction 
agent, in which context it appears to be short acting because of 
redistribution into fatty tissue. Clearance, however, is by hepatic 
metabolism, and when given by prolonged infusion thiopental will 
accumulate, resulting in prolonged recovery, particularly in 
patients with impaired liver function. Immune suppression is also 
possible. 
 
Thiopental is rarely used in intensive care, but may be considered for patients 
receiving mechanical ventilation who are difficult to sedate with other agents, or as 
a second line therapy for refractory intracranial hypertension. Thiopental is also an 
extremely effective anticonvulsant and can be given as a small (25 mg) bolus for the 
Always consider 
alternative drugs (and 
alternatives to drugs) 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.15 
 
treatment of refractory seizures. However, an infusion is preferred for sedation as a 
bolus given to critically ill patients may produce significant hypotension. Hypnotic 
effects are mediated through the GABA receptor at the barbiturate binding site. The 
usual dose by infusion is 2–5 mg/kg/h, with careful monitoring and reduction of 
dose with time. 
 
Measuring plasma concentration of thiopental may be misleading, because the 
receptor concentration may be very different. However, a high plasma 
concentration usually indicates that a significant amount of the drug is bound to 
the receptor. 
 
Alpha-2 agonists 
 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.313–314. alpha-2 adrenergic 
agonists. 
 
Several alpha-2 agonists are available or being investigated. Clonidine is currently 
available in Europe. It is useful in patients suffering from withdrawal symptoms 
after discontinuation of continuous opioid infusions (usually fentanyl) for example. 
 
Dexmedetomidine is a newer agent, licensed for use in the USA. It is a more 
selective alpha-2 agonist than clonidine, which is only a partial alpha-2 agonist and 
has significant alpha-1 agonist effects. Compared to clonidine, dexmedetomidine is 
eight times more potent. In addition, by comparison with other drugs, patients 
sedated with dexmedetomidine can be more easily roused, without being startled. 
 
Further advantages of alpha-2 agonists include the ability to relieve anxiety and 
agitation and promote analgesia without clinically significant respiratory 
depression. Dexmedetomidine can also be used in unintubated surgical patients as 
a sole sedative agent in combination with other analgesics and during elective 
awake neurosurgical procedures. The amount of analgesic needed may be reduced. 
Both drugs may also have a place in the treatment of withdrawal syndromes. 
 
Compared to lorazepam and midazolam, dexmedetomidine (0.2–1.4 mcg/kg/hr) 
may reduce the incidence of delirium and duration of mechanical ventilation. 
However, dexmedetomidine can cause bradycardia and hypotension and is 
expensive. 
 
Maze M, Scarfini C, Cavaliere F. New agents for sedation in the intensive care unit. 
Crit Care Clin 2001; 17(4): 881-897. Review PMID 11762266 
Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al; 
SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With 
Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.16 
 
critically ill patients: a randomized trial. JAMA 2009; 301(5): 489-499. PMID 
19188334 
Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al. Effect of 
sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in 
mechanically ventilated patients: the MENDS randomized controlled trial 
JAMA 2007; 298(22): 2644-2653 PMID 18073360 
 
Neuroleptics 
 
Haloperidol is the most commonly used neuroleptic agent in the critically ill. It can 
be used to sedate an agitated patient with little risk of cardiorespiratory depression. 
The duration of action of haloperidol is about 4–8 hours and the dose is 2.5–5 mg 
repeated as necessary up to about 40 mg. Haloperidol may cause extra-pyramidal 
manifestations and, in addition, can prolong the Q-T interval on the ECG. Rarely 
haloperidol precipitates cardiac arrest. Formerly, droperidol was used as well, but 
has now been withdrawn in many countries. 
 
 Haloperidol is the preferred agent for treatment of delirium in 
the adult as recommended by the ACCM/SCCM. For further information on the 
practice parameters for intravenous analgesia and sedation see following reference. 
 
 
Nasraway SA Jr, Jacobi J, Murray MJ, Lumb PD; Task Force of the American College 
of Critical Care Medicine of the Society of Critical Care Medicine and the 
American Society of Health-System Pharmacists, American College of Chest 
Physicians. Sedation, analgesia, and neuromuscular blockade of the critically 
ill adult: revised clinical practice guidelines for 2002 Crit Care Med 2002; 
30(1): 117–118. PMID 11902252 
 
 As we have seen in the preceding section, there is a relatively wide choice of 
sedative agents for use in the critically ill. Most ICUs, however, tend to use a restricted 
number of such agents. Find out what are the three most commonly used sedatives in your 
own unit, what is the scientific evidence base for this choice and why alternatives are 
chosen for some patients. Determine in the next ten patients in your care the basis for 
selecting a particular agent (or combination of agents) and whether you have been 
consistent in your approach. 
 
Q. For the following patients, which of the following agents would you 
use initially? They are all receiving an opioid for analgesia as well. 
(There may be more than one correct answer). 
 
A. Benzodiazepine (intravenous) 
B. Propofol 
C. Ketamine 
D. Thiopental 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.17 
 
E. Alpha agonist 
F. Neuroleptics 
 
 
1. A patient has a longer than expected femoro-popliteal bypass 
procedure. He comes to the ICU because of the long operation and a 
decrease in core temperature to 35.5 °C. The ICU course is expected to 
be short. 
A. B. C. D. E. F. 
 
A. The preferred option would be: B 
 
2. A 21-year-old female has aspirated at induction of anaesthesia for a 
Caesarean section. Her chest X-rayshows diffuse pulmonary infiltrates 
and she needs an FiO2 of 1 with 10 cm H2O PEEP to maintain a PaO2 > 
8 kPa (60 mmHg). Her heart rate is 140 bpm and her arterial blood 
pressure 80/50 mmHg. Because of a shortage of ICU beds she has been 
kept in theatre anaesthetised with isoflurane for the last six hours and 
has just arrived in the ICU. 
A. B. C. D. E. F. 
 
A. The preferred option would be: A 
 
3. A 65-year-old male has developed multiple organ dysfunction after a 
perforated diverticulum resulting in faecal peritonitis. He also has 
acute respiratory distress syndrome. Currently he needs continuous 
veno-venous haemodiafiltration. Today he has become restless despite 
massive doses of midazolam. His serum is lipaemic. The struggling 
makes mechanical ventilation difficult, the increased venous pressure 
keeps stopping the haemofilter and the patient is at risk of pulling out 
his tracheal tube. 
A. B. C. D. E. F. 
 
A. The preferred options would be: E and F 
 
4. A 28-year-old male is developing increasing intracranial pressure 2 
days after a traumatic brain injury. Heart rate is 110 bpm, mean 
arterial pressure is 90 mm Hg and cerebral perfusion pressure is >60 
mm Hg. The patient is on controlled-assisted ventilation but has some 
spontaneous breathing, which causes further increase of intracranial 
pressure. 
 
A. B. C. D. E. F. 
 
A. The preferred options would be: B 
 
 You should always be able to defend your choice of hypnotic agent. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.18 
 
 
Analgesics 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.312–315. Analgesics. 
Opioid and non-opioid analgesics in the ICU. In: Waldmann C, Soni N, Rhodes A, 
editors. Oxford Desk Reference: Critical Care. Oxford: Oxford University 
Press; 2008. p. 206. ISBN 13: 9780199229581 
 
Pain relief is clearly important. There are two major groups of 
relevant drugs – the opioid-based analgesics and the non-steroidal 
anti-inflammatory agents. 
 
Opioids 
 
The term opiate applies to the naturally occurring analgesics of this group. As more 
synthetic drugs are becoming available, the term opioid is now preferred. Morphine 
is the 'gold standard' to which all other opioids are compared. 
 
Link to ESICM Flash Conference: Bernhard Walder, ‘Is morphine still the 
reference?’ ESICM congress, Vienna 2009 
 
Hall LG, Oyen LJ, Murray MJ. Analgesic agents. Pharmacology and application in 
critical care. Crit Care Clin 2001; 17(4): 899–923, viii Review. PMID 
11762267 
Pandharipande P, Ely EW, editors. Sedation and analgesia in the ICU – 
pharmacology, protocolization, and clinical consequences. Crit Care Clin 
2009; 25(3): 431–636. 
(http://www.sciencedirect.com/science/article/B7RMB-4WN9T8P-
1/2/bfaba97aca1650cdb7918976ab875537) 
 
The commonly used naturally occurring and synthetic opioids are shown below. 
 
 
 
 
 
 
 
 
 
 
 
 
Pain relief is a 
therapeutic priority 
Naturally occurring 
(opiates) 
 
Synthetic 
pethidine 
phenoperidine fentanyl 
 sufentanil alfentanil remifentanil 
morphine codeine 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.19 
 
Opioid receptors 
 
A classification of opioid receptors is shown in the table. Of particular importance 
are the µ-receptors that are responsible for inducing analgesia, as well as some of 
the important adverse effects of opioids such as respiratory depression. 
 
Opioid receptor classification 
 
 
Morphine 
 
The dose of morphine needed to produce analgesia is very variable 
and depends on many factors such as tolerance, as well as 
metabolic and excretory function. The usual dose for an adult 
undergoing mechanical ventilation is 2–5 mg as a bolus or by 
continuous infusion at a rate of 1–10 mg/h. 
 
 
 
 
Morphine is metabolised mostly in the liver by the enzyme uridinosine diphosphate 
(UDP) glucuronyl-transferase system. There are two major metabolites – 
morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G). M-3-G 
may be anti-analgesic whereas M-6-G is a potent analgesic. M-6-G has forty times 
the activity of morphine. Both metabolites may accumulate in renal failure. 
 
 Morphine is often the preferred agent for analgesia in the critically ill 
patient. However its onset time is slow. Consequently small boluses should be 
given several minutes before painful stimulation. 
 
Pethidine (Meperidine) 
 
Pethidine was the first synthetic opioid introduced into clinical practice. The bolus 
dose is 10 mg with an intravenous infusion rate of 10–50 mg/h. A major problem 
with pethidine is the active metabolite, norpethidine (normeperidine) which 
accumulates in renal failure and may cause seizures. For this reason pethidine is 
not recommended in the critically ill. 
 
Friedrich Wilhelm 
Sertürner isolated the 
active constituent of 
poppy juice in 1806 and 
named it after 
Morpheus, the Greek god 
of dreams. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.20 
 
 Many drugs have unexpected side effects. Opioids are no 
exception. 
 
Fentanyl 
 
Fentanyl is a potent synthetic opioid that penetrates membranes quickly and thus 
has a rapid onset of action. It is 75–200 times more potent than morphine. In 
patients needing mechanical ventilation the bolus dose is 50–100 µg and the 
infusion rate 100–200 µg/h. Duration of action is relatively short when first used 
at about 0.5–1 µg/kg/h. However, prolonged infusion may be complicated by 
accumulation, slow recovery and is associated with withdrawal symptoms. De-
escalation dose of methadone could be a useful bridge in such phase. 
 
 Since fentanyl does not cause histamine release the SCCM/ACCM 
recommend fentanyl for analgesia in the haemodynamically unstable patient. 
 
Alfentanil 
 
Alfentanil is one of the newer synthetic opioids. Like all the others it is metabolised 
by the liver. Alfentanil has a short duration of action of about 15 minutes. The bolus 
dose is 250–500 µg with an infusion rate of up to 1–2 mg/h. Of all the opioids 
alfentanil is the least likely to produce active metabolites, although this is 
unproven. 
 
 Small bolus doses of alfentanil may help patients cope with short-
lived, potentially disturbing nursing procedures e.g. turning to prevent pressure 
sores, an advantage in this context being the very rapid onset of action. However, if 
the patient is already on an opioid infusion then a bolus dose of the agent being 
infused may be given. Some opioids (for example morphine) have a long onset of 
action and need to be given well in advance of anticipated pain. 
 
Sufentanil 
 
Sufentanil is another synthetic opioid. It is usually given by continuous intravenous 
infusion at a rate of 0.3–0.09 µg/kg/h, a bolus dose of 1–2 µg/kg can also be given. 
 
Fentanyl, alfentanil and sufentanil are synthetic opioids of the 4-anilidopiperidine 
group that are commonly used in the operating room. These opioids also undergo 
hepatic metabolism, and their continuous infusion can lead to accumulation as well 
as prolonged drug effects. This is especially true in critically ill patients, in whom 
drug clearance may be substantially reduced because of illness, organ dysfunction, 
or concomitant therapy. Therefore, their use is always accompanied by concerns 
regarding drug accumulation, which potentially can lead to prolonged respiratory 
depression and delayed and unpredictable recovery. When these opioids are 
compared, alfentanil is the drug with the most rapid onset of action and the 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.21 
 
shortest duration of effect. However, alfentanil is a substrate for different 
cytochrome P450 3A enzymes, and its metabolism and offset of effect can underlie 
inter-individual variability due to polymorphic enzyme expression. Alfentanil can 
be markedly inhibited by different drugs,including antibiotics and antifungal 
medication. Thus, although single bolus injections of alfentanil are short acting, the 
effects of an infusion of alfentanil in ICU patients are much less predictable. 
Alfentanil is not the ideal short-acting opioid for use in the ICU. 
 
Remifentanil 
 
Remifentanil is a potent ultra short-acting selective µ-opioid receptor agonist and 
was first approved for use as an analgesic agent during induction and maintenance 
of general anaesthesia in 1996. In 2002 remifentanil received approval from the 
European Medicines Agency for provision of analgesia for a duration of up to three 
days in mechanically ventilated ICU patients, aged 18 years or older. Remifentanil 
differs from the other opioids in being metabolised by esterases that are widely 
distributed in all body tissues. Even during the anhepatic period of liver 
transplantation there is little change in pharmacokinetics, graphically illustrating 
the independence of this agent from normal routes of metabolism. The major 
metabolite, remifentanil acid, is a very weak opioid. Indeed, it is so weak that even 
in renal failure it is unlikely to exert any effect. The ability to provide intense 
analgesia with large doses of opioid means that less hypnotic agent is required. 
Patients are more awake and can move around and communicate with their care 
givers. The dose is 6–15 (occasionally 30) µg/kg/h. Because of its unique 
pharmacokinetic profile, remifentanil is characterised by a rapid and uniform 
clearance and a highly predictable onset and offset of effect. Remifentanil has a 
terminal half-life of approximately 10 to 20 minutes, and its context-sensitive half-
life is three to four minutes, regardless of the duration of infusion. Bolus doses are 
not usually recommended because of the risk of bradycardia and hypotension but 
have been studied – see below. It is not licensed for use in patients breathing 
spontaneously and because of its potency can cause sudden apnoea. Its unique 
characteristics make it suitable for patients in whom pain is a limitation for 
weaning. Once the causes of the patient’s pain are resolved, stopping remifentanil 
potentially helps a more rapid discontinuation of sedation. 
 
In post neurosurgical patients in whom serial neurological examination is required, 
its short half-life make a rapid drug free examination possible. 
 
It should be useful even in less severe patients with acute brain damage in whom 
monitoring e.g. intracranial pressure monitoring has not been applied and in 
whom a neurological examination is used to monitor the patient’s status. 
 
 
Park G. Remifentanil in the ICU: a new approach to patient care. Curr Anaesth Crit 
Care 2002; 13: 313–320 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.22 
 
Wilhelm W, Kreuer S. The place for short-acting opioids: special emphasis on 
remifentanil. Crit Care 2008; 12 Suppl 3: S5 Epub 2008 May 14 Review PMID 
18495056 
Casey E, Lane A, Kuriakose D, McGeary S, Hayes N, Phelan D, et al. Bolus 
remifentanil for chest drain removal in ICU: a randomized double-blind 
comparison of three modes of analgesia in post-cardiac surgical patients. 
Intensive Care Med 2010; 36(8): 1380-1385. Epub 2010 Mar 18. PMID 
20237760 
 
Tramadol 
 
Tramadol is an atypical opioid that is an agonist for µ-receptors. It is widely used in 
post-surgical ICUs. It can be given orally as well as intravenously. 
 
Opioid antagonists 
 
Two opioid antagonists are available, naloxone and doxapram, both working by 
different mechanisms. 
 
Naloxone 
 
This is a specific antagonist that binds to the µ-receptor. It completely abolishes the 
effects of all opioids at this site. The dose should be titrated carefully and slowly, 
0.1 mg should be given intravenously every 3–4 minutes. Used without due 
caution, it can cause sudden reversal of analgesia, hypertension and tachycardia 
risking myocardial infarction or cerebrovascular accident in some patients. Acute 
arrhythmias and seizures have also been reported. In others it can cause an acute 
abstinence syndrome, especially those using opioids outside of hospital for 
recreational purposes. 
 
 
A 21-year-old heroin abuser was admitted to the emergency department. He was 
unconscious, barely breathing and cyanosed. Tracheal intubation was immediately 
performed and ventilatory support given. As an opioid overdose was suspected 0.4 
mg of naloxone was administered intravenously. He immediately sat up, pulled out 
his tracheal tube, started swearing and punching the staff. This 'large' dose of 
naloxone produced a sudden abstinence syndrome. In the critically ill, naloxone 
given incautiously will produce reversal of both respiratory depression AND 
analgesia. The pain may cause a sudden outpouring of catecholamines possibly 
resulting in arrhythmias including ventricular fibrillation. 
 
Doxapram 
 
This ‘physiological antagonist’ reverses opioid-induced respiratory depression with 
minimal effects on analgesia, by acting as a respiratory stimulant via the peripheral 
chemo-receptors. A bolus dose of 1–1.5 mg/kg can be used. 
Task 1. Identifying patients’ needs; approach 
to sedation and pain relief p.23 
 
 
Non-steroidal anti-inflammatory drugs 
 
Non-steroidal anti-inflammatory drugs (NSAIDs) are rarely used in seriously ill 
patients because of their side effects (see figure below). These include: 
 
• Anti-coagulant effect – due to interference with platelet function 
• Renal impairment in patients who are hypovolaemic or septic (by 
inhibiting prostaglandin synthesis in response to pre-renal state in the 
kidney) 
• Risk of gastrointestinal bleeding 
• Acute bronchospasm. 
 
Despite these risks in the occasional patient, such as the young adult after trauma 
or major surgery, NSAIDs can be useful. Diclofenac and ketorolac are commonly 
used. Ketorolac can be given intravenously and diclofenac rectally or, in certain 
jurisdictions, intravenously. 
 
The dose of ketorolac is 10 mg six-hourly (for no more than two days) and 
diclofenac 25–50 mg eight-hourly. 
 
Ibuprofen (400–600 mg eight-hourly enterally) is an acceptable alternative. 
 
The adverse effects of non-steroidal anti inflammatory drugs 
 
 
 
Paracetamol (acetaminophen) 
 
This is a non-opioid analgesic. It can be given (500 mg to 1 g) orally, rectally or 
intravenously to patients. The maximum dose in any one day is 4 g. 
 
 A wide variety of analgesics are available in most countries. Those most commonly 
used in European countries are described in this Task, although there are many more. Find 
out from your pharmacist: 
What drugs are available in your hospital that could be used once opioids have been 
discontinued or for less serious pain. 
Look these drugs up in your local formulary to find out exactly what they contain and 
recommendations for their use. 
Task 2. Techniques and routes of administration p.24 
 
2. TECHNIQUES AND ROUTES OF ADMINISTRATION 
 
In the critically ill, absorption via the gastrointestinal tract is often 
unreliable. Most drugs are given intravenously because absorption 
via the intramuscular or subcutaneous routes is also unpredictable. 
 
 
Besides variable absorption the intramuscular route can be complicated by 
haematoma in coagulopathic patients, muscle wasting and the need for frequent 
injections. 
 
 
Drugs absorbed via the GI tract may behave differently from those given 
intravenously because of first pass metabolism by the gut and liver. 
Venous access was proving difficult in a long stay patient on the intensive care unit. 
To preserve the veins that remained all her drugs were changed to the oral route 
and the intravenous lines removed. Morphine was being given for pain relief; this 
was changed to a slow release preparation. The following night, and for the next 
two nights until intravenous administration was restarted the patient experienced 
vivid nightmares. You might like to remember that Morpheus was the mythologicalgod of dreams. 
 
There are several ways of giving drugs intravenously. 
 
Bolus doses – By this means the initial dose can be titrated to produce the 
desired effect which can then be maintained by repeat doses. Unnecessary 
administration is avoided. It does, however, have the disadvantage that the 
relatively rapid increase in the concentration of the drug may lead to adverse 
effects such as cardiorespiratory depression. Minimal equipment is needed, but 
intermittent bolus doses are more time-consuming for the nursing staff. 
 
 
Several years ago a patient was admitted to the intensive care unit with an acute 
exacerbation of chronic obstructive pulmonary disease. She made good progress, 
but awoke one night and started to cough. This distressed her and she became 
hypoxic and hypercarbic as a consequence. At that time the ICU resident, who had 
heard about the new drug propofol but was uncertain how to use this agent, gave a 
bolus dose of 50 mg which calmed the patient down, stopped the coughing and 
straining, allowing the PaO2 to increase and the PaCO2 to decrease. When she 
awoke a few minutes later, the coughing gone, the only sedation she needed was 
some comforting words from the nurse at her bedside. No more sedatives were 
needed for six or seven hours. Remember even short-acting drugs do not always 
need to be given by infusion. More importantly, if you don't know a drug well, find 
out before using it! 
 
 
The technique chosen for drug administration should be determined primarily by 
the needs of the patient. 
 
The route by which 
a drug is given is 
second only in 
importance to the 
choice of drug 
Task 2. Techniques and routes of administration p.25 
 
Continuous intravenous infusion. This is the method most commonly used 
for sedative drugs. It is convenient for the staff and avoids sudden fluctuations in 
blood concentration. On the other hand, accumulation may be a problem, 
especially when drug elimination is adversely affected by critical illness. When the 
drug is stopped, prolonged coma may result. A further risk is infusion pump 
malfunction or misuse. In some 'critical incident' surveys, syringe pump 'errors' 
have been found to be very common. This can be avoided by regular monitoring 
and by allowing the patient to recover from the sedation each day. 
 
Daily interruption of sedative infusion 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.311–312. Assessing the level of 
sedation. 
 
An alternative sedation strategy that can be applied is daily interruption of sedative 
infusions (DIS). In 2000, Kress and coworkers showed that temporarily stopping 
sedative (midazolam or propofol) and analgesic (morphine) infusions until the 
patient was able to follow three or four simple tasks or was agitated led to 
significant reductions in duration of mechanical ventilation, shorter ICU length of 
stay and use of fewer diagnostic tests for unexplained changes in mental status. 
 
There is evidence that sedative and analgesic agents should be interrupted once 
daily unless there is contraindication such as pain or patient distress or there is a 
raised ICP (see below) or ongoing neuromuscular blockade. Once the drugs are 
interrupted, the ICU team must be vigilant for evidence of patient distress, which 
may manifest as overt physical agitation, isolated haemodynamic lability 
(hypertension or tachycardia), or ventilator asynchrony. Providers are then 
encouraged to administer bolus drug dosing to control symptoms, and restart both 
sedative and analgesic drugs at half the previous infusion doses with subsequent 
titration to the desired depth of sedation. DIS can be combined with a spontaneous 
breathing trial. Close observation during DIS is required to reduce the risk of self-
extubation and other consequences of agitation. 
 
In patients with acute neurological disease at immediate risk of severe intracranial 
hypertension and or global or regional ischaemia, a scheduled neurological 
examination is not recommended. It should be done only if its benefits are believed 
to outweigh any potential for adverse effect. The level of intracranial pressure, 
pupil reactivity to light, CT findings and, importantly, the level of therapy applied 
to control ICP all are useful guides to plan daily sedation interruption. 
 
In patients in whom intracranial pressure is controlled, and associated clinical and 
imaging findings suggest an improvement of initial damage, a daily interruption, or 
a progressive decline of infusion rate, is suggested. This should be useful to set new 
sedation levels once negative symptoms appear. 
Task 2. Techniques and routes of administration p.26 
 
Daily wakening may not be suitable for neonates and young children. In these 
patients, continuous infusions of short-acting, more predictable agents such as 
remifentanil and propofol can be used. 
 
Daily interruption of sedation (DIS) does not work in all ICUs. If your ICU is 
different, be aware of why. 
 
 
Sessler CN, Pedram S. Protocolized and target-based sedation and analgesia in the 
ICU. Crit Care Clin 2009; 25(3): 489–513, viii Review. PMID 19576526 
Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Crit Care 
2008; 12 Suppl 3: S6 Epub 2008 May 14. Review. PMID 18495057 
Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, et al. 
Efficacy and safety of a paired sedation and ventilator weaning protocol for 
mechanically ventilated patients in intensive care (Awakening and Breathing 
Controlled trial): a randomised controlled trial. Lancet 2008; 371(9607): 
126–134. PMID 18191684 
Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative 
infusions in critically ill patients undergoing mechanical ventilation. N Engl J 
Med 2000; 342(20): 1471–1477. PMID 10816184 
Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of 
continuous i.v. sedation is associated with prolongation of mechanical 
ventilation. Chest 1998; 114(2): 541–548 PMID 9726743 
 
If your ICU has regular 'critical incident' surveys find out the incidence of syringe 
pump 'errors'. 
 
Nurse-controlled analgesia – a syringe of sedative or analgesic is push-button 
operated by the nurse when the patient is judged to need sedation or analgesia. A 
complex and expensive syringe pump is required. As the patient recovers, the 
pump can be programmed to allow patient-controlled analgesia. 
 
 PCAS/NCAS pumps offer good control of pain although they are expensive. Find 
out from your hospital stores or the manufacturers the cost of the pumps in your unit. 
 
An approach to practice is to use sedative and analgesic drugs initially in small 
bolus doses and assess their effects. If the drug produces the desired effect for a 
reasonable period of time then management proceeds with repeated small 
intravenous bolus doses. If, however, the bolus doses need to be repeated 
frequently, then an intravenous infusion is started. 
Task 2. Techniques and routes of administration p.27 
 
Target-controlled infusion (TCI). Although this is more established for 
anaesthesia, it is described for intensive care. See link to ESICM Flash Conference: 
Claude Martin, ‘Sedation (target controlled infusion)’ ESICM congress, Vienna 
2009 
 
Other routes of administration 
 
Epidural infusion 
 
Infusions of local analgesic agents often combined with opioids can give very 
effective analgesia e.g. in the case of fractured ribs or thoracic or abdominal 
wounds. 
 
 
Local anaesthetics can be toxic if infused into the epidural space and not 
adequately eliminated. A patient who was involved in a road traffic accident and 
sustained fractured ribs on the left side resulting in a small flail segment had a 
thoracic epidural catheter placed and an infusion of bupivacaine started. This made 
the patient comfortable. On the third evening he became acutely confused. When 
seen by the doctor he wasstanding on his bed swinging his intravenous infusion 
round above his head! He thought the doctors were mistreating him and wanted to 
go to the police station to complain. His confusion was attributed to his 
bupivacaine and the epidural stopped (it had become disconnected anyway). After 
some gentle persuasion he sat down in his bed. Four hours later he was again 
rational. The epidural was restarted when his pain returned – at a lower dose. 
 
Combination of drugs 
 
Drugs may behave in different ways if given concurrently with another agent. Three 
different types of interaction are described. In the following description 1 equals 
the effect of a drug. 
 
Additive effects 1+1=2 
Antagonistic effects 1+1=0 
Synergistic effects 1+1=3 
 
The phenomenon of synergy is commonly exploited when prescribing antibiotics. 
Recently, the importance of synergy has been appreciated with regard to drugs 
used for sedation. 
 
Q. Name two synergistic combinations of sedative and analgesic drugs 
and explain why they are synergistic. 
Task 2. Techniques and routes of administration p.28 
 
 
A. Propofol and midazolam, thiopental and midazolam. The mechanism for the synergy is 
thought to be at the GABA receptor. However, remember that propofol also acts on lipid 
membranes. The combination of safer drugs, for example midazolam with propofol, may 
help to reduce dosage of propofol which is a drug with a risky side effect profile. 
 
Opioids and midazolam. 
The mechanism for this is unknown. 
 
 
An 18-year-old soldier was riding his motorcycle when a car emerged from a side 
road without stopping and hit him. He suffered a fractured tibia and a torn tibial 
artery. On arrival at hospital he went straight to the operating room where he 
underwent a long and bloody operation to repair his leg. For this reason he was 
transferred to the ICU to recover. There was, however, concern about the vascular 
repair. Although he was ready for tracheal extubation the surgeons asked that he be 
kept 'sedated' and on a ventilator in case he needed to return to the operating room 
urgently. 
 
Q. What action might you have taken in these circumstances? 
 
A. Normally, keeping young men sedated when they only have an isolated limb injury is 
difficult. In this patient, the critical care team used a synergistic combination of a low dose 
of propofol with intermittent bolus doses of midazolam. He was also given intermittent 
doses of morphine for pain relief. 
 
Q. Could he have had a morphine infusion? How fully does synergy 
between these drugs work? 
 
A. Arguably an infusion of morphine could have been used, since this patient was not at 
risk of accumulating the drug or the metabolite. Although morphine and midazolam are 
also synergistic, the additional combination does not further reduce the effective doses i.e. 
three-way synergy does not occur. 
Task 3. Neuromuscular blockade p.29 
 
3. NEUROMUSCULAR BLOCKADE 
 
 
Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. Saunders 
Ltd; 2008. ISBN: 978-0-7020259-6-9. p.317–318. Muscle relaxation. 
 
The use of neuromuscular blockers (NMBs) in the ICU has decreased substantially 
in recent years. In the occasional patient, NMBs may be needed in addition to 
sedatives. Indications for the use of NMBs include: 
 
• Resuscitation (including tracheal intubation) 
• Ventilatory modes that are difficult for the patient to tolerate (such as 
high PEEP, prolonged I:E ratio) 
• Extreme hypoxia/hypercarbia 
• Raised intracranial pressure 
• Ventilator/patient dyssynchrony when appropriate sedation and 
analgesia has failed (rare). 
 
You may find the following texts of particular value in this connection: 
 
 
Murray MJ, Cowen J, DeBlock H, Erstad B, Gray AW Jr, Tescher AN, McGee WT, 
Prielipp RC, Susla G, Jacobi J, Nasraway SA Jr, Lumb PD; Task Force of the 
American College of Critical Care Medicine (ACCM) of the Society of Critical 
Care Medicine (SCCM), American Society of Health-System Pharmacists, 
American College of Chest Physicians. Clinical practice guidelines for 
sustained neuromuscular blockade in the adult critically ill patient Crit Care 
Med 2002; 30(1): 142–156. PMID 11902255 
Muscle relaxants. In: Waldmann C, Soni N, Rhodes A, editors. Oxford Desk 
Reference: Critical Care. Oxford: Oxford University Press; 2008. p. 210. ISBN 
13: 9780199229581 
 
 Neuromuscular blockers are very potent and will stop a patient's breathing. Before 
you give these drugs you must be competent at managing an airway and tracheal 
intubation. If you have not received this training, seek expert help. Resuscitation and 
specialist equipment must be available to deal with a (difficult) intubation. Before giving a 
neuromuscular blocker, the patient must be unconscious; hypnotic drugs are nearly always 
required. 
 
The use of neuromuscular blockers in mechanically ventilated patients may be 
considered under two main headings: 
 
• Cerebral protection – mainly by preventing increases in intracranial 
pressure caused by coughing and straining. This intervention makes 
Task 3. Neuromuscular blockade p.30 
 
sense only as an acute intervention. Routine use of neuromuscular 
blockers is not necessary once the patient is appropriately sedated and 
with analgesia. Sometimes boluses of NMBs before and during 
transportation might increase its safety. 
• Mechanical ventilation – of relevance in patients with lungs that are 
difficult to ventilate and who may need unusual ventilatory modes, such 
as reversed inspiratory–expiratory ratio. Neuromuscular blockers are 
not, however, always needed to tolerate reversed I:E ratio ventilation. 
 
Specific agents 
 
 Muscle relaxant drugs should never be used alone! They should always be 
used in conjunction with sedatives and analgesics 
 
A wide choice of neuromuscular blocking agents is available for use in the critically 
ill patient of which the following are most frequently used. 
 
Atracurium 
 
Atracurium undergoes spontaneous, ester hydrolysis (Hoffman degradation) to 
metabolites that are inactive at the neuromuscular junction. One metabolite, 
laudanosine, that accumulates in hepatic and renal failure, has been implicated in 
convulsions in animals, but never in man. Histamine release occasionally occurs 
with bolus administration, and tachyphylaxis may occur with prolonged 
administration. Recovery of neuromuscular transmission occurs predictably in less 
than one hour regardless of the duration of the infusion. 
 
The dose of atracurium is 0.5 mg/kg for tracheal intubation and 0.5 mg/kg/h as an 
infusion. Atracurium may be indicated in those at risk of critical care weakness 
since the frequency of this complication appears to be less with this drug. 
 
Cisatracurium 
 
Atracurium is a racemic mixture of ten steroisomers. One of them, cisatracurium, 
makes up only 15% of the isomers but contributes 60% of the activity. It also 
releases much less (virtually none) histamine, resulting in greater cardiovascular 
stability. A pure preparation of this isomer is now being made available. 
 
The dose of cisatracurium is initially 0.1 to 0.20 mg/kg with an infusion 
maintenance dose of 3 µg/kg/min or 0.18 mg/kg/h. Like atracurium it is 
eliminated by a Hoffman reaction and metabolism is independent of liver function. 
 
Pancuronium 
 
This is a neuromuscular blocking agent with a steroid structure. It can be given as a 
bolus dose of 0.1 mg/kg (which will last for one hour) or an infusion of 4–10 mg/h. 
The major disadvantage of pancuronium is that it can cause a tachycardia. It also 
accumulates in renal failure causing prolonged blockade. These complications and 
Task 3. Neuromuscular blockade p.31 
 
the risk of critical care weakness have limited its use in many ICUs. However, the 
latest guidelines still recommend pancuronium unless vagolysis is contraindicated 
or there is renal or hepatic disease. 
 
Vecuronium 
 
Again this neuromuscular blocking agent has a steroid structure. In addition, it has